Our previous studies provided evidence that guinea pigs that are vitamin C deficient and those that have been fasted, but supplemented with vitamin C, are equivalent with respect to the mechanisms responsible for decreased collagen and proteoglycan synthesis. Sera from both groups contain a circulating factor that inhibits these functions and DNA synthesis in cultured connective tissue cells and inhibition is reversed by insulin-like growth factor (IGF)-I. The presence of the inhibitor in sera was associated with an increase in low molecular weight IGF binding proteins (IGFBPs) that can inhibit binding of IGF-I to its cellular receptor. We have identified them as IGFBP-1 and IGFBP-2 with antibodies that were produced using peptides with conserved IGFBP-2 sequences or native IGFBP-1 purified from rat hepatoma cells, as antigens. The mRNAs for these IGFBPs in liver are increased early during fasting and soon after weight loss commences during vitamin C deficiency, which is in agreement with the appearance of these IGFBPs in sera, as measured on ligand blots with [125I]IGF-I. The increase in IGFBP mRNA concentrations occurs prior to or concommitant with the time when type I collagen mRNA concentrations in bone and skin begin to decrease during the nutritional deficiencies. In contrast, the decline in IGF-I mRNA concentrations occurs more slowly than the changes in the mRNAs for collagen and the IGFBPs. These results are compatible with an in vivo role for IGFBPs as inhibitors of collagen synthesis during fasting and vitamin C deficiency in guinea pigs, independently of the level of circulating IGF- I.